state of the art standard of care for resectable NSCLC surgical approach for resectable NSCLC

state of the art standard of care for resectable NSCLC surgical approach for resectable NSCLC Dominique H. Grunenwald, MD, PhD Professor Emeritus in Thoracic and Cardiovascular surgery Pierre & Marie Curie University. Paris. France

surgical approach for resectable nsclc which patient? -which resection? -which technique? -which surgeon? standard of care guidelines recommendations

what do we expect from the surgery? the best local control i.e. a complete therapeutic response i.e. a chance of cure provided it could remain a harmless procedure a better survival and quality of life than no treatment other treatments no surgery in the context of multimodal therapy

surgery = extirpation

questions before considering surgery operable patient? resectable tumour? type of resection? which approach? therapeutic pathway? depends on clinical performance TNM staging local invasion tumour size and location state of the art

definitions an "operable" patient has an acceptable risk of death or morbidity a "resectable" tumour can be completely excised by surgery with clear pathological margins

risks from surgery increase with age and comorbidities does the patient have the functional pulmonary reserve to tolerate the proposed resection to maintain a reasonable quality of life? because surgical resection offers little benefit if the patient suffers postoperative pulmonary insufficiency or death

assessment by a multidisciplinary team (MDT) thoracic surgery pulmonology oncology imaging nuclear medicine pathology consideration of the patient s general condition comorbidity cardiac condition lung condition diagnostic and therapeutic indications

assessment by a multidisciplinary team (MDT) the thoracic surgeon pulmonology oncology imaging nuclear medicine pathology consideration of the patient s general condition comorbidity lung condition cardiac condition diagnostic and therapeutic indications and acceptance

definitions an "operable" patient has an acceptable risk of death or morbidity a "resectable" tumour can be completely excised by surgery with clear pathological margins "early stage"

what is early stage lung cancer? this refers to cancers that are caught early enough that they have the potential to be cured with surgery the TNM stage influences survival after surgery Goldstraw P, et al. J Thorac oncol 2007;2:706-14

TNM Classification for Lung Cancer (8th Edition) T Classification: importance of tumor size highlighted T1 T2 T3 T1a ( 1 cm), T1b (>1 to 2 cm), and T1c (>2 to 3 cm) T2a (>3 to 4 cm) and T2b (>4 to 5 cm) (>5 to 7cm) T4 > 7 cm (prev. T3) T2 involvement of main bronchus regardless of distance from carina (prev. T2/3) T2 partial and total atelectasis/pneumonitis (prev. T2/3) T4 diaphragm invasion (prev. T3) deletion of mediastinal pleural invasion as a T descriptor N Staging unchanged, new descriptors proposed for prospective testing and validation p N1 single (pn1a) and multiple (pn1b) nodal station involvement pn2 M Staging M1a M1b M1c pn2a1 (single pn2 nodal station involvement without pn1 disease, skip metastasis pn2a2 with single station pn2 and pn1 involvement pn2b with involvement of multiple pn2 nodal stations unchanged single metastasis in a single organ multiple metastases

stage groupings (8th edition) Stage IA N0 and 3 cm IA1, IA2, IA3 (a category for each cm in size) Stage IB N0 and >3 to 4 cm Stage IIA N0 and >4 to 5cm Stage IIB N0 and >5 to 7 cm or N1 and smaller tumors Stage IIIA N0 and > 7cm or others T4 N1 and T3-T4 N2 and T1a-T2b Stage IIIB N2 and T3-4 N3 and T1a-T2b Stage IIIC N3 and T3-T4 Stage IVA Any T Any N with M1a and M1b Stage IVB > 1 extrathoracic metastasis (M1C)

early stage lung cancer in the TNM 8th edition stage IA : IA 1 T1a N0 M0 ( 1 cm) very early IA2 T1b N0 M0 (>1 to 2cm) IA3 T1c N0 M0 (>2 to 3cm) stage IB : T2a N0 M0 (>3 to 4cm) stage IIA : T2b N0 M0 (>4 to 5 cm) stage IIB : T3 N0 M0 (>5 to 7cm) early T1a-c N1 M0 T2a-b N1 M0 stage IIIA: T4 N0 M0 locally advanced T3-4 N1 M0 T1a-2b N2 M0 stage IIIB T3-4 N2 M0 locally advanced T1a-T2b N3 M0 stage IVA-B : Any T, any N, M1a-b-c surgery no surgery

questions depends on operable patient? clinical performance YES resectable tumour? TNM staging YES type of resection? local invasion which approach? tumour size and location therapeutic pathway? state of the art

type of resection depends on tumor size and/or location (T factor) wedge resection segmentectomy lobectomy pneumonectomy along with systematic en-bloc dissection of mediastinal lymph node stations!

type of resection depends on local invasion (T factor) lobectomy + extended resection extended pneumonectomy

bilobectomy (right side) LSD LID LM indication parenchyma bronchus LSG LIG

which resection for stage I tumours? stage IA : IA 1 T1a N0 M0 ( 1 cm) very early IA2 T1b N0 M0 (>1 to 2cm) IA3 T1c N0 M0 (>2 to 3cm) stage IB : T2a N0 M0 (>3 to 4cm) stage IIA : T2b N0 M0 (>4 to 5 cm) stage IIB : T3 N0 M0 (>5 to 7cm) early T1a-c N1 M0 T2a-b N1 M0 stage IIIA: T4 N0 M0 locally advanced T3-4 N1 M0 T1a-2b N2 M0 stage IIIB T3-4 N2 M0 locally advanced T1a-T2b N3 M0 stage IVA-B : Any T, any N, M1a-b-c surgery potential to be cured with surgery alone Ginsberg RJ and Rubinstein LV 1995 the gold standard in stage I is an anatomic lobar resection (Lung Cancer Study Group) no surgery

but the extent of parenchymal resection remains an area of evolution several situations where sublobar resection should be reasonably considered as primary treatment for early-stage nsclc patients with limited pulmonary reserve poor physical conditions multiple primary nsclcs Asamura H. and Donington J. J Thorac Oncol 2017;12:1188-9

an evolving paradigm? sublobar resection: a movement from the Lung Cancer Study Group 1995 LCSG consensus : lobectomy = gold-standard (stage I nsclc) enhancements in imaging technology screening programs minimally invasive surgical resection reduced perioperative morbidity and mortality equivalent oncologic effectiveness to open surgery larger cohorts of localized early-stage disease challenging lobectomy as a standard for small tumors Blasberg JD, et al. J Thorac Oncol 2010;5:1583-93

sublobar resection? wedge resection anatomical segmentectomy

survival following lobectomy and limited resection for the treatment of stage I nsclc <= 1cm in size: a review of SEER data (Surveillance, Epidemiology, and End Results registry) 2,090 patients limited resect. (segment. or wr) 688 (33%) no difference in outcomes among patients treated with lobectomy vs limited resection overall survival HR : 1.12 (95% CI: 0.93-1.35) lung cancer-specific survival HR: 1.24 (95% CI: 0.95-1.61) in favor Kates M, et al. Chest 2010

sublobar resection is equivalent to lobectomy for clinical stage 1A lung cancer in solid nodules (International Early Lung Cancer Action Program) nsclc with a diameter of 30 mm or less (stage 1) n=347 10-yr survival sublobar res. (n=53) 85% lobectomy (n=294) 86% P =.86 cancers 20 mm or less in diameter P =.45 equivalent survival for patients with clinical stage IA nsclc in the context of computed tomography screening for lung cancer in favor Altorki NK, et al. J Thorac Cardiovasc Surg 2014;147:754-62 (I-ELCAP)

16 papers / 116 (1 meta analysis, 1 RCT) represented the best evidence to answer the clinical question. there is evidence that wedge resections, compared to segmentectomies and lobectomies, lead to lower survival and higher recurrence rates lobectomy is still recommended for younger patients with adequate cardiopulmonary function. against

expected results of clinical trials CALGB 140503 JCOG0802/WJOG4607L will see!

questions depends on operable patient? clinical performance YES resectable tumour? TNM staging YES type of resection? local invasion DECIDED which approach? tumour size and location therapeutic pathway? state of the art

Grunenwald D, et al. Ann Thorac Surg 1997;63:563-6 approach depends on tumor size and location open thoracotomy vats uniportal vats robotic others (transmanubrial, ) and $$$ as well

minimally invasive lobectomy video-assisted thoracic surgery (VATS) has become a common surgical technique VATS generally means operating by using thoracoscopy with a minimal number of small incisions and without rib spreading assumption that it has an oncologic outcome equivalent to that of open thoracotomy but is a less invasive method scientifically supported comparisons between VATS and open thoracotomy with randomized controlled trials have been scarcely reported Asamura H. and Donington J. J Thorac Oncol 2017;12:1188-9

open or mis*? safety? * mini-invasive surgery

intraoperative vascular risks Watanabe A : 21 pulmonary artery injuries / 185 vats (11%) * Tatsumi A : 1 death from intraoperative bleeding / 118 vats ** *Watanabe A. et al. Kyobu Geka 2003;56:943-8 **Tatsumi A. et al. Jpn Journal Thorac Cardiovasc Surg 2003;51:646-50**

video-assisted thoracoscopic versus open thoracotomy lobectomy in a cohort of 13,619 patients Nationwide Inpatient Sample database lobectomy thoracotomy (n = 12,860) vats (n = 759) vats = higher incidence of intraoperative complications (p = 0.04) Gopaldas RR, et al. Ann Thorac Surg 2010;89:1563-70 minimal incision = delay in control of bleeding vats worse?

propensity score analysis comparing videothoracoscopic lobectomy with thoracotomy: a french nationwide study open thoracotomy 24,811 (95.1%) VATS 1,278 (4.9%) end points 30-day postop. death atelectasis and pneumopathy other postoperative complications hospital length of stay os and dfs vats ns reduced ns decreased from 2.4 days not influenced vats equivalent? Pagès PB, et al. et al. Ann Thorac Surg 2016;101:1370-8

video-assisted thoracoscopic surgery versus open lobectomy for primary nsclc: a propensity-matched analysis of outcome from the ESTS database (28771 patients) propensty matched groups n=2721 lobectomy thoracotomy vats p no. % no. % patients 2721 2721 total complications 792 29 863 32 0.0357 major CP complic. 316 16 435 20 0.0094 atelectasis (bronchosc.) 65 2.4 150 5.5 <0.0001 initial ventilation < 48h 18 0.7 38 1.4 0.0075 wound infection 6 0.2 17 0.6 0.0218 in-hosp. mortality 27 1 50 1.9 0.0201 postop. hospital stay (days) 7.8 9.8 0.0003 vats better? VATS is associated with a lower incidence of complications compared with thoracotomy. Falcoz PE, et al. Eur J Cardiothorac Surg 2016;492:602-9

thoracoscopic lobectomy produces long-term survival similar to that with open lobectomy in cases of nsclc: a propensity-matched analysis using a population-based cancer registry (5222 patients) open lobectomy 3058 patients (58.6%) thoracoscopic lobectomy 2164 (41.4%) propensity matching produced 1848 patients in each group 5-year OS rates for open lobectomy 65.5% for thoracoscopic lobectomy 68.7% ns similar long-term survival in the setting of lung cancer thoracoscopic lobectomy is an acceptable surgical treatment of lung cancer vats equivalent? Wang BY, et al. J Thorac Oncol 2016;11:1326-34

a national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer (nodal upstaging occurs when unsuspected lymph node metastases are found during the final evaluation of surgical specimens) Danish Lung Cancer Registry 1,513 pts VATS 717 (47%) thoracotomy 796 (53%) nodal upstaging 281 pts (18.6%) thoracotomy higher N1 upstaging (13.1% vs 8.1%; p<0.001) N2 upstaging (11.5% vs 3.8%; p<0.001) no difference in OS between VATS and thoracotomy (hazard ratio, 0.98; 95% confidence interval, 0.80 to 1.22, p=0.88). Licht PB, et al. Ann Thorac Surg 2013;96:943-9

nodal upstaging during lung cancer resection is associated with surgical approach retrospective review c-stage 1a p-stage 1a p thoracotomy 1964 36,4% 30.5% 0.0002 vats 500 47,4% 38% 0.0002 thoracotomy VATS p overall nodal upstaging (%) 9.9 4.8 0.0002 increased survival was found with VATS 0.0042 selection bias may play a role the improved quality of life measures associated with VATS may explain survival improvement despite lower surgical upstaging! Martin JT, et al. Ann Thorac Surg 2016;101:238-44

nodal upstaging during lung cancer resection is associated with surgical approach retrospective review c-stage 1a p-stage 1a p thoracotomy 1964 36,4% 30.5% 0.0002 vats 500 47,4% 38% 0.0002 vats worse? thoracotomy VATS p overall nodal upstaging (%) 9.9 4.8 0.0002 increased survival was found with VATS 0.0042 vats better? selection bias may play a role the improved quality of life measures associated with VATS may explain survival improvement despite lower surgical upstaging! Martin JT, et al. Ann Thorac Surg 2016;101:238-44

nodal upstaging is more common with thoracotomy than with vats during lobectomy for early-stage lung cancer: an analysis from the national cancer data base (16,983 patients) nodal upstaging more frequent in the open group (12.8% vs. 10.3%; p < 0.001) propensity score matching : 4437 patients in each group upstaging remained more common for open approaches however, in academic/research facility, the difference in nodal upstaging no longer significant (12.2% vs. 10.5%, p = 0.08) vats equivalent? vats worse? Medbery RL, et al. J Thorac Oncol 2016;11:222-33

to conclude on vats lobectomy large national or regional databases VATS lower incidence of postoperative complications shorter length of hospital stay by 1 to 2 days some reports higher incidence of nodal upstaging observed in open possibility of insufficient nodal evaluation in VATS these conclusions were derived from retrospective studies therefore, harbor hidden biases that may affect the outcome further randomized studies required to demonstrate the prognostic equivalence and any differences in QOL or postoperative complications. Asamura H. and Donington J. J Thorac Oncol 2017;12:1188-9

robot-assisted thoracic surgery (RATS) retrospectively reported to be equivalent to VATS in all measures of quality for treatment of lung cancer no randomized trials have reported the comparative data between RATS and VATS/thoracotomy for lung cancer Asamura H. and Donington J. J Thorac Oncol 2017;12:1188-9

use and outcomes of minimally invasive lobectomy for stage I nsclc in the national cancer data base (30,040 patients) open versus minim. invasive surgery (MIS [VATS and robotic]) propensity score matching: 9,390 patients in each group MIS have increased 30-day readmission rates p < 0.01 shorter median hospital length of stay p < 0.01 improved 2-yr survival p = 0.04 nodal upstaging ns 30-day mortality ns VATS versus robotic lobectomy for clinical T1-2, N0 nsclc propensity score matching : 1,938 patients in each group no difference with regard to nodal upstaging, 30-day mortality, and 2-year survival Yang CF, et al. Ann Thorac Surg 2016;101:1037-42

comparison of video-assisted thoracoscopic surgery and robotic approaches for clinical stage I and stage II nsclc using the sts database clinical stage I or stage II nsclc 1,220 robotic lobectomies 12,378 VATS procedures robotic lobectomy more comorbidities longer operative times robotic and vats equivalent complications hospital stay 30-day mortality nodal upstaging Louie BE, et al. Ann Thorac Surg 2016; Sep;102(3):917-24

uniportal vats Gonzales-Rivas D. WCLC 2016

the future : uniportal robotic platform Intuitive Sugical da Vinci Sp Single Port Robotic Surgical system

surgical resection of lung cancer - standard of care stage IA : IA 1 T1a N0 M0 ( 1 cm) early IA2 T1b N0 M0 (>1 to 2cm) IA3 T1c N0 M0 (>2 to 3cm) stage IB : T2a N0 M0 (>3 to 4cm) stage IIA : T2b N0 M0 (>4 to 5 cm) stage IIB : T3 N0 M0 (>5 to 7cm) early T1a-c N1 M0 T2a-b N1 M0 stage IIIA: T4 N0 M0 locally advanced stage T3-4 I & N1 II M0 tumours - T1a-2b surgeryn2 M0 stage IIIB - T3-4 open N2, vats M0 locally advanced - T1a-T2b lobar or N3 sublobar? M0 stage IVA-B : Any T, any N, M1a-b-c surgery no surgery

surgical resection of lung cancer - standard of care stage IA : IA 1 T1a N0 M0 ( 1 cm) early IA2 T1b N0 M0 (>1 to 2cm) IA3 T1c N0 M0 (>2 to 3cm) stage IB : T2a N0 M0 (>3 to 4cm) stage IIA : T2b N0 M0 (>4 to 5 cm) stage IIB : T3 N0 M0 (>5 to 7cm) early T1a-c N1 M0 T2a-b N1 M0 stage IIIA: T4 N0 M0 locally advanced stage T3-4 I & N1 II M0 tumours - T1a-2b surgeryn2 M0 stage IIIB - T3-4 open N2 or M0 vats locally advanced - T1a-T2b lobar or N3 sublobar? M0 stage IVA-B : Any T, any N, M1a-b-c no surgery

state of the art? controversial situations stage IA : IA 1 T1a N0 M0 ( 1 cm) stage III-N2 early IA2 T1b N0 M0 (>1 to 2cm) surgery or not IA3? T1c N0 M0 (>2 to 3cm) stage upfront IB surgery : or T2a induction N0 M0 (>3? to 4cm) stage risks IIA? : T2b N0 M0 (>4 to 5 cm) stage locally IIB advanced : T3 T3/4 N0 M0 (>5 to 7cm) early surgery? T1a-c N1 M0 T2a-b N1 M0 stage IIIA: T4 N0 M0 locally advanced T3-4 N1 M0 T1a-2b N2 M0 stage IIIB T3-4 N2 M0 locally advanced T1a-T2b N3 M0 stage IVA-B : Any T, any N, M1a-b-c surgery no is there a role for surgery in locally advanced nsclc? surgery

what we know from evidence based medicine in N2 disease dramatic benefit with induction chemotherapy compared to surgery alone in two small-scale studies [Roth, Rosell, 1994] no benefit in large european randomized study in stage IIIA category [Depierre, 2002] stage IIIA benefits from adjuvant chemotherapy following "complete resection" [Arriagada, 2004; Douillard, 2006] nothing on radiotherapy (Lung-ART still ongoing) nothing on surgery

N2 disease paradigms and opinions mediastinal downstaging from induction is the most powerful positive prognostic factor for survival after surgery [Betticher, 2003; Albain, 2009] rt should be considered the preferred locoregional treatment for pts with stage IIIA-N2 nsclc responders to induction ct [Van Meerbeck, 2007] good candidates for surgery may still be appropriately managed by using resection rather than radiation [Vansteenkiste, 2007] the role of surgery is not clearly defined [Roy and Donington, 2007]

N2 disease paradigms and opinions mediastinal downstaging from induction is the most powerful positive prognostic factor for survival after surgery [Betticher, 2003; Albain, 2009] rt should beno considered standard the preferred of care locoregional treatment for pts with stage IIIA-N2 nsclc responders to induction ct [Van Meerbeck, 2007] case by case discussion good candidates in for a surgery tumor mayboard still be appropriately managed by using resection rather than radiation [Vansteenkiste, 2007] the role of surgery is not clearly defined [Roy and Donington, 2007]

locally advanced nsclc are not "surgical", an evolving paradigm? locally advanced T3-4 superior sulcus tumor

en bloc vertebrectomy / intralesional approach upfront surgery / induction rt-ct pers. MDA Toronto yr 2006 2009 2013 induction none, ct none ct-rt surg. technique en bloc intralesional en bloc pts 34 31 48 partial vert. 28 16 38 total vertebr. 6 15 10 R0 res. (%) 88 56 88 mortality (%) 3 5 6 5-yr surv. (%) 24 27 61

state of the art 1. evidence suggests that triple modality therapy with complete resection of Pancoast tumors with involvement of the spine offers an advantage over other therapeutic modalities 2. given the negative prognostical influence of N2 nodal status, those patients must be precluded from surgery 3. highly selected centers and surgical teams

what about the surgical quality? lymph node dissection as an example

rationale for a minimum number of lymph nodes removed with nsclc resection: correlating the number of nodes removed with survival in 98,970 patients resection without evidence of pathologic nodal involvement lobectomy 83.9 % sublobar resection 12.7 % pneumonectomy 2.8 % the number of LNs removed correlated with increasing tumor size and extent of resection the number of LNs removed correlated with improved survival removal of <10 LNs was associated with a 12 % increased risk of death (p < 0.001) Samavoa AX, et al. Ann Surg Oncol 2016;23(Suppl 5):1005-11

Surgical Quality importance of surgical quality measures (QMs) in nsclc was highlighted in 2016 National Cancer Database stage I (1) anatomic resection (2) operation within 8 weeks of diagnosis (3) R0 resection (4) more than 10 lymph nodes sampled 99% of resections met at least one QM only 22% satisfied all four median OS no QMs 31 months 4 QMs 89 months compliance with basic QMs was associated with improved OS Asamura H. and Donington J. J Thorac Oncol 2017;12:1188-9

quality measures in clinical stage I nsclc : improved performance is associated with improved survival (133,366 patients) quality measures (no.) 1 2 3 4 % of patients 99.7 94.9 68.6 22.5 more likely to meet all four measures income of at least $38,000/year insurance type (private insurance vs. Medicare) centers with at least 38 cases/year academic institutions clinical stage IB patients national adherence to quality measures is suboptimal guideline compliance is strongly associated with survival efforts should be instituted by national societies to improve adherence. Samson P, et al. Ann Thorac Surg 2017;103:303-11

surgical quality in clinical stage IIIA adherence to four QMs (1) neoadjuvant therapy (2) lobectomy or more extensive procedure (3) R0 resection (4) >10 lymph nodes sampled only 12.8% of stage IIIA resections satisfied all QMs median OS no QMs 12 months 4 QMs 43.5 months compliance with QMs remained a strong independent predictor of survival Asamura H. and Donington J. J Thorac Oncol 2017;12:1188-9

recommendations ESMO Postmus PE, et al. Ann Oncol 2017;28(Suppl.4) BTS-SCTS Lim E, et al. Thorax 2010;65:iii1-iii27 ACCP Howington JA, et al. Chest 2013;143(5_suppl):e278S-e313S

Suggested algorithm for locoregional lymph node staging ESMO Clinical Practice guidelines. Postmus PE, et al. Ann Oncol 2017;28(Suppl.4)

treatment of early stages (stages I and II) - surgery ESMO Clinical Practice guidelines. Postmus PE, et al. Ann Oncol 2017;28(Suppl.4)

ESMO Clinical Practice guidelines. Postmus PE, et al. Ann Oncol 2017;28(Suppl.4)

take home messages 1. the therapeutic decision starts in a multidisciplinary tumor board including a thoracic surgeon 2. detailed TNM staging according to the 8th edition determines the choice of treatment 3. surgery should be offered to all patients with stage I and II 4. anatomical resection is preferred 5. lymph node dissection should conform to standard specifications

take home messages (cont'd) 6. surgical approach should be appropriate to the expertise of the surgeon 7. pneumonectomy should be avoided where possible 8. patients with limited pulmonary reserve can be considered for sublobar resection as an acceptable alternative to lobectomy 9. compliance with surgical quality measures is associated with improved survival 10. cancer surgery must be performed by board-certified thoracic surgeons